Substituted p-(1-hydroxyalkyl) phenethyl alcohols

ABSTRACT

Substituted phenethyl alcohols, e.g., p-(2,2-dimethyl-1hydroxypropyl)phenethyl alcohol, are prepared by reducing a corresponding phenyl acetic acid and are useful as hypolipidemic agents.

United States Patent Houlihan et al.

SUBSTITUTED P-( l-HYDROXYALKYL) Pl-IENETHYL ALCOHOLS Inventors: William J. Houlihan, Mountain Lakes; Jeffrey Nadelson, Lake Parsippany, both of NJ.

Assignee: Sandoz-Wander, lnc., Hanover, NJ.

Filed: June 4, 1973 Appl. No.: 366,763

US. Cl...... 260/618 R, 260/465 R, 260/515 A, 260/515 R, 260/592, 260/613 D, 260/618 D, 260/6l8 H, 260/665 G, 424/340, 424/343 Int. Cl. C07c 43/20, CO7c33/02 Field of Search 260/618 D, 618 H, 618 R, 260/613 D [451 Feb. 18,1975

Primary Examiner-Joseph E. Evans Assistant ExaminerD. B. Springer Attorney, Agent, or FirmGerald D. Sharkin; Robert S. Honor [57] ABSTRACT Substituted phenethyl alcohols, e.g., p-(2,2-dimethyll-hydroxypropyl)phenethyl alcohol, are prepared by reducing'a corresponding phenyl acetic acid and are useful as hypolipidemic agents.

4 Claims, N0 Drawings 1 SUBSTITUTED P-(l-HYDROXYALKYL) PHENETHYL ALCOHOLS This invention relates to substituted phenethyl alcohols which exhibit hypolipidemic activity. lnparticular,

2.5 to 3.5 hours. The compounds of formula (I) are recovered by conventional techniques, e.g., evaporation.

The compounds of formula (II) are prepared according to the following reaction scheme:

it relates to substituted p-( l-hydroxyalkyl)phcnethyl alcohol, and processes for their preparation.

The compounds of this invention may be represented by the formula:

whet-e3 R and R are as set out above.

The compounds of formula (II) are prepared by hydrolyzing compounds of formula (III) with aqueous mineral acids. When R, is hydrogen or halo, it is pre- CHZCHQOH ferred that concentrated mineral acid be used. When R is lower alkoxy. it is preferred that a dilute mineral R (I) .acid be employed. The acid can be hydrochloric acid. 1 sulfuric acid. phosphoric acid and the like. The particular acid used is not critical but hydrochloric acid is pre- H C ferred. The aqueous solvent can be water or a mixture 3 C 0!! of water and a water soluble or l h game so vent. e.g.. t e lower alkanols. The preferred solvent is water, alwhere though the particular solvent used is not critical. The R1 represents hydrogen halo having an atomic temperature of the reaction is also not critical, but it 18 weight of about 19 to 36 and straight chain lower preferred -that the reaction be carried out from about alkoxy Le" Straight chain alkoxy having 1 to 4 can 20 to 80 C., espec allyat the reflux temperature of the b0" atoms eg methoxy ethoxy, or the like, and solvent. The reaction 15 run for about 12 to 72 hrs., R and R each independently represent alkyl having preferably to 9 The product refmvered by l or 2 Carbon atoms, i'c" methyl or ethyl. conventional techniques, e.g., recrystallizatmn. The compounds of formula (I) are prepared accord- The compounds of formula (III) are prepared acing to the following reaction scheme: 40 cording to the following reaction scheme:

2 2 CH Cl-i Ol'l R reducing agent R :0 H R a c p-a 3 2 (II) i where R,. R and R are as set out above. CH Br CH CN The compounds of formula (I) are prepared by re- 2 2 ducing a compound of the formula (ll) with an alkali metal hydride reducing agent such as sodium aluminum R hydride or lithium aluminum hydride. the latter being MCN especially preferred. The reaction is carried out in the presence of an inert organic solvent such as the ethers, =o c=0 cg. tctrahydrofuran or dicthylether, preferably tetra- H H hydrofuran. Although the temperature of the reaction 3 2 3 2 is not critical, it is prefered that the reaction be run from about 0 to l()()C., especially at the reflux temperature of the solvent. The reaction is run from about (IV) (III) where v ligrams per kilogram of body weight per diemof the M represents an alkali metal, preferably 50- compound for 6 days. At the end of this period, the anidium or potassium and mals are anesthetized with sodium hexobarbital and h 2 and R3 are as set b abovebled from the carotid arteries. Serum or plasma sam- Th Compounds of formula re prepared by ples are collected, and 1.0 ml. samples of the serum are treating c mp n of formula With an alkali 'added to 9.0 ml. redistilled isopropanol. Two autoanametal cyanide such as sodium cyanide, potassium cyalyzer cupsful of a mixture of zeolite-copper hydroxide nide, and the like, preferably potassium cyanide, in the and Lloydds reagent (Kessler, G., and Lederer, H., presence of an aqueous organic solvent or anhydrous l965, Techni S sium, Mediad Inc, New York, dimethylsulfoxide. The preferred solvents are the aque 1O [3 5347]) are added, and the mixture is a en o l ous-lower alkanols Such as ater and e anol, eth hour. Cholesterol and triglyceride levels are deterno] and the like, and water-dioxane. The temperature mined imultaneously on the same sample Tec hni. of the reaction is not critical but it is preferred that the n 'N 24 A (cholesterol) and N-78 (triglyceride) process be carried out at a temperature between about rh d l g The mean totalserum cholesterol levels to especially at e reflux'temperatul'e of l are'then computed and the hypocholesterolemic activh y The reaction is fun for about hours; ity is expressed as the fall in cholesterol levels as a perp y' to 5 hours- The Prochlet is recovered y centage of the'control level. The change in serum tri- Conventibnal techniques, g-i evaporation glycer ide levels induced by the drugis computed as a T e compounds of formula are p p percentage of the control triglyceride levels.

cording to the following reactionscherne f For such usage, the compounds (I) may be combined cs I v I CH Br bromin ating agent c =o I l H C-CR H C-(!-R p I 3 a R3 3 I t (-Iv) 1 a 1 he e 1; 2 and R3 are as set out abovewith a pharmaceutically acceptable carrier or ad uvant The mpo of formula are p p y and may be administered orally or parenterally as such treating a compound of formula With a r m nat- 'or admixed with conventional pharmaceutical carriers. lhg agent in the PreSence of an inert Organic solvent They may be administered in such forms astablets, disand free radical initiator. The brominating agent which ibl owder granules, capsules, syrups and elixirs can be used isbromine, N-bromosucci nimide. and parenterallyas solutions, suspensions, dispersions, bromo ph halamide, -b omo-aoetam e and th i eemulsions and the like, e.g., a sterile injectable aqueous The particular agent used is not critical, but N- 40 solution. The dosage will vary depending upon the bromosuccinamide is preferred. In the preferred p mode of administration utilized and the particular com-- cess, the free radical initiator used is an organieor inorpound l d,

gable Peroxide, especially bel'lzoyl Peroxide The reae- The hypolipidemic effective dosage of compounds tion can also be carried out under ultraviolet light. Al- (1) l d i h ll vi ti n of lipidemia may varythough the particular solvent usedis not critical, the d di on th ti ular compound employed and p solvents are the halogenated hydrocarbons the severityof the condition being treated. However. in Such as methylene dichloride, chloroform, Carbon general, satisfactory results are obtained when the raehloride and the like, although the aromatic y compounds of formula (I') are administered at a daily carbons Such as benzene also be p y The dosage of from about 4.0 milligrams to about 250 millitemperature of the reaction is not critical, and can grams per kil f i l body weight, preferably range from 20 to 80C., but reflux temperature of the given in divided doses two to four times a day, or in sussolvent is preferred. The reaction is run for about 12 to r i d release f F t large mammals, the total 48 hours; p ra y 18 to 25 u S- The P o u is daily dosage is from about 300 milligrams to about covered by conventional techniques, e'.g., crystalliza- 4,000 milli ms. Dosage 'forms suitable for internal tion. r use comprise from about 75 to about 2,000 milligrams M ny f he mp n f form l (V) r kn w of the active compound in intimate admixture with a and may be prepared by methods describ in the W solid or liquid pharmaceutically acceptable carrier or ature. The compounds of formula (IV) not specifically dil nt,

disclosed may be-prepared by analogous methods from A representative formulation suitable for oral adminknown starting materials. istration 2 to 4 times a day for the treatment of lipide- The compounds of formula are Useful e mia is a capsule prepared by standard encapsulating they possess pharmacological activity in animals. In h i ues which contains the following:

particular, they are useful as hypolipidemic agents in the treatment of lipidemia in particular hyperlipoproteincmia as indicated by the fall in cholesterol and triglyceride levels in male albino Wistar rats weighingingredients ll s l l0-l30 g. nitially. The rats are maintained on drugp (22 dimmhyl Lhwlmxwmm free laboratory chow diet for seven days and then d1 phcnethyl alcohol vided into groups of 8 to 10 animals. .Each group with kaolin) 200 the exception of the control is then given orally 30 m l;

EXAMPLE 1 a-bromo-p-pivaloyl toluene.

To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there isadded 10 ml. (1.17 mole) of 4-bromotoluene in 650 ml. dry tetrahydrofuran, the reaction is started and the remainder of the bromotoluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 1 /2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tctrahydrofuran at a rate that maintains the temperature at to 5C. The solution is stirred for an additional 1 /2 hours at 0 and then at room temperature for 18 hours. The mixture is then cooled to 0 and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 'ml. of ether is added to the organic phase which is then washed respectively with 100 ml. 2N hydrochloric acid, 100 ml. percent sodium bicarbonate solution and '100 ml. saturated sodium chloride. The organic layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p. 8084 C/0.7 mm,n =1.5108). A'mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then' added to 157.8 g. (0.886 mole) N-bromosuccinimide,-

4.0 g. (0.016 mole) benozyl peroxidean'd 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting precipitate is washed with carbon tetrachloride. The solvents are removed in vacuo and the resulting oil is distilled in vacuo to give a-bromo-p-pi'valoyl toluene (b.p. l24-132C/0.7 mm, n *=1.5546-V.P.C. 96 percent monobromo 4 perc'ent-dibromo).

Following the above procedure and using-in place of 4-bromotoluene equivalent amounts of:

a. 4-bromo-2-chlorotoluene,

b. 4-bromo-2-methoxytoluene, or

c. 4-bromo-2-fluorotoluene, there is obtained a. a-bromo-2-chloro-4-pivaloyl toluene,

b. a-bromo-2-methoxy-4-pivaloyl toluene, or

c. or-bromo-2-fluoro-4-pivaloyl toluene, respectively.

EXAMPLE 2 p-pivaloyl phenyl acetonitrile.

A solution of 39.2 g. (0.700 mole) potassium cyanide in 40 ml. of water is warmed to 50C. and a solution of a-bromo-p-pivaloyl toluene in 85 ml. ethanol is then' added dropwise at such a rate as to maintain the temperature at 50C. After the addition is complete the mixture is refluxed for 4 hours. The excess ethanol is removed in vacuo and the resulting residue is treated with ether/water. The layers are separated and the ether is washed with cold 50 percent sulfuric acid,

water and sodium bicarbonate, then the-ether layer is there is obtained a. 2-chloro-4-pivaloyl phenyl acetonitrile, b. 2-methoxy 4 pivalo yl phenyl acetonitrile, or

c. 2-fluoro-4-pivaloyl phenyl acetonitrile, respectively.

' EXAMPLE 3 acid and the resulting solid is then recrystallized from' hot benzene to give p-pivaloyl phenyl acetic-acid, m.p. (1111l2C.).

Following the above procedure and using in place of p-pivaloyl phenyl acetonitrile an equivalent amount of a. 2-chloro-4-pivaloyl phenyl acetonitrile, or b. 2-fluoro-4-pivaloyl phenyl acetonitrile, there is obtained a. 2-chloro-4-pivaloyl phenyl acetic acid, or

b. 2-fluoro-4-pivaloyl phenyl acetic acid, respectively. v Again following the above procedure and using in place of p-pivaloyl phenyl acetonitrile .an equivalent amount of 2-methoxy-4-pivaloyl phenyl. acetonitrile and dilute hydrochloric acid in place of concentrated hydrochloric there is obtained 2-methoxy-4-pivaloyl phenyl acetic acid.

EXAMPLE 4 p-(2.2-dimcthyllahydroxypropyl)phenethyl alcohol.

To a solution of'5.2 g. (0.137 mole) oflithium aluminum hydride in 35 ml. of tetrahydrofuran cooled in an ice-bath, there is added dropwise 10 g. (0.045 mole) of p-pivaloyl phenyl acetic acid in ml. of tetrahydrofuran over a periodof about 30 minutes. After the addition is complete, the resulting mixture is refluxed for 3 hours and then cooled in an ice-bath. while quenching successively with 31.2 ml. of ethyl acetate, 10.4 ml. of sodium hydroxide and 15.6 ml. of water. The resulting mixture is then treated with anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with petroleum ether containing a small amount of ether to give p-(2,2-dimethyl-1-hydroxypropyl)-phenethyl alcohol, m.p. l34-l37C.

Following the above procedure and using in place of p-pivaloyl phenyl acetic acid, an'equivalent amount of a. 2-chloro-4-pivaloyl phenyl acetic acid,

b. 2-fluoro-4-pivaloyl phenyl acetic acid, or

c. 2-methoxy-4-pivaloyl phenyl acetic acid there is obtained a. 2-chloro-4-(2,2-dimethyl-l-hydropropyl)- phenethyl alcohol,

b. 2-fluoro-4-( 2,2-dimethyll -hydroxypropyl phenethyl alcohol, or i s c. 2-methoxy-4-(2,2-dimethyl-1-hydroxypropyl)- phenethyl alcohol, respectively.

cohol of this example is an effective hypolipidemic agent when orally administered to an animal suffering from lipidemia at a dosage of from about 75 to 250 milligrams four times per day.

What is claimed is:

1. A compound of the formula 7 8 CH CH H where R is as defined in claim 1. R 3. A compound of the formula cn cn oa Cl. where R, represents hydrogen, halo having an atomic weight of about 19 to 36 orstraight chain lower alkoxy, and R and R each independently, represent lower alkyl H O having 1 to 2 carbon atoms. {(k 03 2. A compound of the formula 2 CHZCHQOE where R and R are as defined'in claim 1. H C v 4. The compound of claim 1 which is p-(2,2-

3 I v a C 05 v dlmethyll-hydroxyprop yl)-phenethyl alcohol. 3 3 

1. A COMPOUND OF THE FORMULA
 2. A compound of the formula
 3. A compound of the formula
 4. The compound of claim 1 which is p-(2,2-dimethyl-1-hydroxypropyl)-phenethyl alcohol. 